title: Endoplasmic reticulum stress in wake-active neurons progresses with aging.
abstract: Fragmentation of wakefulness and sleep are expected outcomes of advanced aging. We hypothesize that wake neurons develop endoplasmic reticulum dyshomeostasis with aging, in parallel with impaired wakefulness. In this series of experiments, we sought to more fully characterize age-related changes in wakefulness and then, in relevant wake neuronal populations, explore functionality and endoplasmic reticulum homeostasis. We report that old mice show greater sleep/wake transitions in the active period with markedly shortened wake periods, shortened latencies to sleep, and less wake time in the subjective day in response to a novel social encounter. Consistent with sleep/wake instability and reduced social encounter wakefulness, orexinergic and noradrenergic wake neurons in aged mice show reduced c-fos response to wakefulness and endoplasmic reticulum dyshomeostasis with increased nuclear translocation of CHOP and GADD34. We have identified an age-related unfolded protein response injury to and dysfunction of wake neurons. It is anticipated that these changes contribute to sleep/wake fragmentation and cognitive impairment in aging.
authors.affiliation: Division of Sleep Medicine, Center for Sleep & Circadian Neurobiology, School of Medicine, University of Pennsylvania, 125 S. 31st Street, Philadelphia, PA 19104, USA. naidoo@mail.med.upenn.edu
authors.forename: Nirinjini
authors.initials: N
authors.lastname: Naidoo
authors.forename: Jingxu
authors.initials: J
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Polina
authors.initials: P
authors.lastname: Fenik
authors.forename: Jie
authors.initials: J
authors.lastname: Lian
authors.forename: Ray
authors.initials: R
authors.lastname: Galante
authors.forename: Sigrid
authors.initials: S
authors.lastname: Veasey
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D051742:Transcription Factor CHOP / Q000378:metabolism; D014851:Wakefulness / Q000502:physiology*
chemical_list: C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1